Synaptic Proteome Alterations in the Primary Auditory Cortex of Schizophrenia

Importance Findings from unbiased genetic studies have consistently implicated synaptic protein networks in Schizophrenia ( Sz ), but the molecular pathology at these networks and their potential contribution to the synaptic and circuit deficits thought to underlie disease symptoms remain unknown. Objective To determine if protein levels are altered within synapses from primary auditory cortex ( A1 ) of subjects with Sz; and if so, are these differences restricted to the synapse or present throughout the grey matter? Design A paired case-control design was utilized for this study. Biochemical fractional – targeted Mass Spectrometry ( MS ) was used to measure the levels of >350 proteins in A1 grey matter homogenate and synaptosome preparations, respectively. All experimenters were blinded to diagnosis at every stage of sample preparation, MS analysis, and raw data processing. The effects of postmortem interval ( PMI ) and antipsychotic drug treatment on protein levels were assessed in mouse and monkey models, respectively. Setting All cases were recruited from a single site, The Allegheny County Office of the Medical Examiner, and all tissues were processed at the University of Pittsburgh. Participants Brain specimens from all subjects were obtained during autopsies conducted at the Allegheny County Office of the Medical Examiner after receiving consent from the next-of-kin. An independent panel of experienced clinicians made consensus Diagnostic and Statistical Manual of Mental Disorders Fourth Edition diagnoses. Unaffected comparison subjects underwent identical assessments and were determined to be free of lifetime psychiatric illness. Each Sz subject was matched by sex, and as closely as possible for age and PMI, with one unaffected comparison subject. Main Outcomes and Measures Primary measures were homogenate and synaptosome protein levels and their co-regulation network features. Prior to data collection we hypothesized: 1. That levels of canonical postsynaptic proteins in A1 synaptosome preparations would differ between Sz and control subjects; and 2. That these differences would not be explained by changes in total A1 homogenate protein levels. Results Mean subject age was 48 years for both groups with a range of 17-83; each group included 35 males and 13 females; mean PMI was 17.7 hours in controls and 17.9 in Sz. We observed robust alterations (q < 0.05) in synaptosome levels of canonical mitochondrial and postsynaptic proteins that were highly co-regulated and not readily explained by postmortem interval, antipsychotic drug treatment, synaptosome yield, or underlying alterations in homogenate protein levels. Conclusions and Relevance Our findings indicate a robust and highly coordinated rearrangement of the synaptic proteome likely driven by aberrant synaptic, not cell-wide, proteostasis. In line with unbiased genetic findings, our results identified alterations in synaptic levels of postsynaptic proteins, providing a road map to identify the specific cells and circuits that are impaired in Sz A1.